1. Field of the Invention
The present invention relates to a method for delaying the onset of Alzheimer's Disease and for treating or delaying the onset of other amyloidosis-related diseases/disorders.
2. Description of the Related Art
It is estimated that ten percent of persons older than 65 years of age have mild to severe dementia. Alzheimer's Disease (AD) is the most common cause of chronic dementia with approximately two million people in the United States having the disease. Although once considered a condition of middle age, it is now known that the histopathologic lesions of Alzheimer's disease (i.e., neuritic amyloid plaques, neurofibrillary degeneration, and granulovascular neuronal degeneration) are also found in the brains of elderly people with dementia. The number of such lesions correlates with the degree of intellectual deterioration. This high prevalence, combined with the rate of growth of the elderly segment of the population, make dementia (and particularly AD) one of the most important current public health problems.
Deposition of cerebral amyloid is a primary neuropathologic marker of Alzheimer's disease. This amyloid is composed of a 40-42 amino acid peptide called the amyloid beta protein (A.beta.) (Glenner et al., 1984). Amyloid deposits in AD are found mainly as components of senile plaques, and in the walls of cerebral and meningeal blood vessels (Robakis et al., 1994).
Molecular cloning showed that A.beta. comprises a small region of a larger amyloid precursor protein (APP) (Robakis et al., 1987; Weidemann et al., 1989). Briefly, this is a type I integral membrane glycoprotein having a large extracytoplasmic portion, a smaller intracytoplasmic region, and a single transmembranous domain. APP undergoes extensive post-translational modifications (Pappolla et al., 1995; Robakis et al., 1994) prior to the secretion of its N-terminal portion (Sambamurti et al., 1992; Robakis et al., 1994). Physiologic processing of APP involves cleavage within the A.beta. sequence by an unidentified enzyme, alpha-secretase (Anderson et al., 1991). Smaller quantities of APP molecules are cleaved at two other sites that could potentially produce amyloidogenic secreted or membrane bound APP (Robakis et al., 1994). A.beta. is also produced during normal cellular metabolism (Haass et al., 1992; Shoji et al., 1992).
There is some controversy as to whether amyloid causes AD; however, three main lines of evidence have strengthened the amyloid hypothesis. The first piece of evidence is provided by the identification of several point mutations within the APP gene. These mutations segregate within a subgroup of patients afflicted with a familial form of the disorder and thus suggest a pathogenetic relationship between the APP gene and AD (Chartier-Harlin et al., 1991; Kennedy et al., 1993). Secondly, amyloid deposition temporally precedes the development of neurofibrillary changes (Pappolla et al., 1996) and this observation is also consistent with a link between amyloid and neuronal degeneration. Finally, it has been shown that A.beta. is toxic to neurons (Yankner et al., 1990; Behl et al., 1992; Behl et al., 1994; Zhang et al., 1994), a finding that also strengthened the hypothesis that the amyloid peptide may contribute to the neuronal pathology in AD.
If amyloid deposition is a rate-limiting factor to produce AD, then all factors linked to the disease will either promote amyloid deposition or enhance the pathology that is provoked by amyloid. The likelihood of amyloid deposition is enhanced by trisonomy 21 (Down's syndrome) (Neve et al., 1988; Rumble et al., 1989), where there is an extra copy of the APP gene, by increased expression of APP, and by familial Alzheimer's Disease (FAD)-linked mutations (Van Broeckhoven et al., 1987; Chartier-Harlin et al., 1991; Goate et al., 1989; Goate et al., 1991; Murrell et al., 1991; Pericak-Vance et al., 1991; Schellenberg et al., 1992; Tanzi et al., 1992; Hendriks et al., 1992; Mullan et al., 1992). Some of these mutations are correlated with an increased total production of A.beta. (Cai et al., 1993; Citron et al., 1992) or specific overproduction of the more fibrillogenic peptides (Wisniewski et al., 1991; Clements et al., 1993; Suzuki et al., 1994) or increased expression of factors that induce fibril formation (Ma et al., 1994; Wisniewski et al., 1994). The relationship between amyloid and the genetics of Alzheimer's Disease is well reviewed by Selkoe (1996). Collectively, these findings strongly favor the hypothesis that amyloid deposition is a critical element in the development of AD (Hardy 1992).
The finding that A.beta. has neurotoxic properties has provided a possible connection between amyloid accumulation and neurodegeneration. Because of the close association between aging and AD and the similarities in the neuropathology of both conditions, oxidative stress has been proposed to play a role in the pathogenesis of AD lesions.
Several investigators demonstrated that oxygen free-radicals (OFRs) are related to the cytotoxic properties of A.beta. (Behl, 1992; Behl, 1994; Harris et al., 1995; Butterfield et al., 1994; Goodman and Mattson, 1994). Such findings are important, since markers of oxidative injury are topographically associated with the neuropathologic lesions of AD (Pappolla et al., 1992; Furuta et al., 1995; Smith et al. 1995; Pappolla et al., 1996). Because of these observations, antioxidants have been proposed as potential therapeutic agents in AD (Mattson, 1994; Hensley et al., 1994; Pappolla et al., 1996).
Melatonin is a hormone which is synthesized and secreted primarily by the pineal gland and it acts both as a neurotransmitter and neurohormone. Being lipid soluble, it rapidly crosses the blood brain barrier and other tissues. Once released from the pineal gland, which is highly vascularized, melatonin enters the general circulation and the cerebrospinal fluid (CSF). Melatonin acts on the central and peripheral nervous system as well as on peripheral endocrine target tissues and has been implicated in many human disorders. Some disorders are known to be linked to chronobiologic abnormalities.
The in vivo levels of melatonin show a cyclical, circadian pattern with highest levels occurring during the dark period of a circadian light-dark cycle. Melatonin is involved in the transduction of photoperiodic information and appears to modulate a variety of neural and endocrine functions in vertebrates, including the regulation of reproduction, body weight and metabolism in photoperiodic mammals, the control of circadian rhythms and the modulation of retinal physiology. Melatonin has been administered in humans to re-synchronize circadian rhythms that are out of phase with local environmental cues, i.e., chronobiological therapy. For example, sleep/wake disorders associated with rapid crossing of time zones (jet lag), changes in work shifts, or those experienced by blind people can be treated with melatonin or melatonin analogs (U.S. Pat. Nos. 4,600,723; 4,665,086; and 5,242,941). Given orally in doses of 0.25-10 mg, melatonin has been used successfully to treat circadian disorders due to jet lag (Arendt et al., 1987; U.S. Pat. Nos. 4,600,723 and 5,242,941). Moreover, timed oral melatonin treatment apparently shifts the human circadian clock according to a phase-response curve (U.S. Pat. No. 5,242,941).
Interestingly, melatonin also exhibits antioxidant properties (Reiter, 1995), but, in contrast to conventional antioxidants, this hormone has a proposed physiologic role in the aging process (Pierpaoli, 1991; Pierpaoli et al., 1991) and decreased secretion of melatonin with aging is documented (Iguchi et al., 1982; Dori et al., 1994). There are reports of more profound reductions of melatonin secretion in populations with dementia than in non-demented controls (Souetre et al., 1989; Mishima et al., 1994). It has been suggested that altered secretion levels of the hormone may partially reflect the loss of daily variation in the concentration of melatonin in the pineals of elderly individuals and AD patients (Skene et al., 1990). These facts regarding melatonin are in sharp contrast with conventional anti-oxidants which despite their reported cytoprotective characteristics have no comparable correlates with the pathophysiology of human aging.
The effects of melatonin are complex. In addition to its OFR scavenging properties, melatonin interacts with calmodulin (Benitez-King et al., 1993), microtubular components (Bentiez-King et al., 1993), and is reported to increase the activity of the intrinsic cellular antioxidant defenses (Huerto-Delgadillo et al., 1994). Melatonin, with its recently established antioxidant properties, was shown to be effective in preventing death of cultured neuroblastoma cells as well as oxidative damage and intracellular Ca.sup.+2 increases induced by a cytotoxic fragment of amyloid .beta.-protein (Pappolla et al., 1997). The use of melatonin for its cytoprotective effect in enhancing survivability of cells that have been subjected to the cytotoxic effects of amyloid .beta.-protein as well as for treating patients afflicted with Alzheimer's Disease is disclosed in allowed U.S. patent application Ser. No. 08/801,301, which has not yet issued. Thus, the protective antioxidant effect of melatonin is only used therapeutically after the onset of Alzheimer's Disease.
Like amyloid fibrils, abnormal protein folding into .beta.-sheet structures to form amyloid-like deposits is also widely believed to be the cause of prion-related encephalophathies, such as Creutzfeldt-Jakob disease (CJD) and Gerstmann-Straussler-Scheinker disease (GSS) in humans, scrapie in sheep and goats, and spongiform encephalopathy in cattle.
The cellular prion protein (PrP.sup.c) is a sialoglycoprotein encoded by a gene that in humans is located on chromosome 20 (Oesch et al., 1985; Basler et al., 1968; Liao et al., 1986; Meyer et al., 1986; Sparkes et al., 1986; Bendheim et al., 1988 and Turk et al., 1988). The PrP gene is expressed in neural and non-neural tissues, the highest concentration of mRNA being in neurons (Chesebro et al., 1985; Kretzschmar et al., 1986; Brown et al., 1990; Cashman et al., 1990 and Bendheim et al., 1992).
The translation product of PrP gene consists of 253 amino acids in humans (Kretzschmar et al., 1986 and Pucket et al., 1991), 254 in hamster and mice or 256 amino acids in sheep and undergoes several post-translational modifications. In hamsters, a signal peptide of 22 amino acids is cleaved at the N-terminus, 23 amino acids are removed from the C-terminus on addition of a glycosyl phosphatidylinositol (GPI) anchor, and asparagine-linked oligosaccharides are attached to residues 181 and 197 in a loop formed by a disulfide bond (Turk et al., 1988; Hope et al., 1986; Stahl et al., 1987 and Safar et al., 1990).
In prion-related encephalophathies, PrP.sup.c is converted into an altered form designated PrP.sup.Sc, that is distinguishable from PrP.sup.c in that PrP.sup.Sc (1) aggregates; (2) is proteinase K resistant in that only the N-terminal 67 amino acids are removed by proteinase K digestion under conditions in which PrP.sup.c is completely degraded; and (3) has an alteration in protein conformation from .alpha.-helical for PrP.sup.Sc to an altered form (Oesch et al., 1985; Bolton et al., 1982; McKinley et al., 1982; Bolton et al., 1984; Prusiner et al., 1984 and Bolton, 1987).
Several lines of evidence suggest that PrP.sup.Sc may be a key component of the transmissible agent responsible for prion-related encephalopathies (Prusiner, 1991) and it has been established that its protease-resistant core is the major structural protein of amyloid fibrils that accumulate intracerebrally in some of these conditions (Brendheim et al., 1984; DeArmond et al., 1985; Kitamoto et al., 1986; Robert et al., 1986; Ghetti et al., 1989; Tagliavini et al., 1991 and Kitamoto et al., 1991)
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